: A rare case of prosthetic valve infective endocarditis caused by Aerococcus urinae

Infective endocarditis (IE) is a serious and life-threatening cardiac condition, most commonly caused by staphylococci, Streptococcus viridans, and enterococci. However, in special settings, IE can be caused by rare organisms. Here we present a case of IE caused by Aerococcus in a 75-year-old man with a bioprosthetic aortic valve. urinae Aerococcus is a gram-positive, catalase-negative microorganism and is usually urinae an isolate of complicated urinary tract infections in the elderly male population.  . Improvements in diagnostic testing including use of matrix-assisted laser desorption ionization– a time of flight mass spectrometry (MALDI-TOF MS) have played an important role in isolating Aerococcus.


Introduction
IE is a serious and potentially life-threatening condition. Expedite recognition, diagnosis, and treatment is critical. The diagnosis of IE is based on Dukes criteria or its modifications 1 . Risk factors for IE include advanced age (> 60 years), male gender, history of intravenous drug use, poor dentition, structural or valvular heart disease and presence of prosthesis. Here, we describe a rare case of IE secondary to Aerococcus urinae, a gram-positive, catalasenegative coccus that grows in clusters. Aerococcus urinae is a rare organism and since its isolations in 1967, has been increasingly recognized as a causative pathogen of urinary tract infections and rarely IE, as can be seen in this case. In the past, reported cases showed poor outcome; however recent Swedish epidemiological study reported the favorable outcome 2 .

Case report
A 75-year-old Caucasian man presented to his local hospital with malaise, fever, and nausea for five days. He had a bio prosthetic aortic valve replacement for mixed aortic valve disease 12 years ago; further significant past medical history included placement of a permanent pacemaker for complete heart block, right total hip replacement, hypertension and benign prostatic hyperplasia (BPH). The patient had no history of smoking, alcohol consumption or illicit drug use. The patient had no recent surgeries or dental work, and the review of systems was unremarkable. The physical exam revealed vital parameters of HR 97 bpm regular, BP 134/87, the temperature of 101.5°F, respiratory rate of 18 per minute and oxygen saturation of 96% on room air. On precordial auscultation, a systolic and a diastolic murmur were heard in the aortic area, mild bi-basal crackles, but no jugular venous distention or peripheral edema. The rest of the physical exam was unremarkable. The labs showed a normal white cell count (WCC) of 9.9 × 10 6 /L, elevated C-reactive protein to 214.9 and a hemoglobin of 11.2 g/dl), the other labs were unremarkable. His mid-stream urine showed WCC < 20; red cell count (RCC) of 20-50 and it grew mixed organisms, all considered part of the normal flora. Chest X-ray, CT scan of the brain, thorax, abdomen, and pelvis did not show any source of infection.
The patient was empirically commenced on IV piperacillintazobactam and vancomycin. Blood cultures collected at the time of admission grew Aerococcus urinae in both bottles. A repeat set of blood cultures corresponding to a spike of fever in the following 24 hours also grew Aerococcus urinae in both bottles; all cultures were sensitive to ampicillin (MIC 0.064 mg/L) and gentamicin (MIC 2 mg/L).
A trans-thoracic echocardiogram showed mild aortic regurgitation and mitral regurgitation with no clear vegetation, however, transesophageal echocardiogram (TOE) showed normal left ventricular function with moderate aortic regurgitation due to large mobile vegetation on the bio-prosthetic aortic valve. There was no peri-valvular abscess or features of the paravalvular abscess noted (See Image 1a and 1b). Pacemaker lead and right-sided valves were not involved.

Amendments from Version 1
We added new references to the introduction about favorable outcome to IE caused by Aerococcus.
We added also new references to the introduction about diagnosing IE based on the Dukes criteria or their modifications.
We also discussed the rapid & sudden deterioration of the patient. The appropriate arrangements of treatment were prepared but the patient deceased prior to surgery.
We also included a reference confirming that surgery isn't indicated most of these cases.
Discussion about MALDI-TOF MS remained, as we wish our readers to know that improved methods of isolation are important and could help with management Abstract and introduction re-written to reflect changes as per recommendations. Clinical presentation, echocardiographic findings, and positive blood cultures fulfilled Duke's criteria for IE. The patient was managed as prosthetic aortic valve endocarditis from Aerococcus urinae with IV amoxicillin 2 grams every 4 hours, and gentamicin 1 mg/kg twice daily as per hospital guidelines for IE. IV antibiotic therapy for six weeks in total with possible surgery for prosthetic valve replacement was planned.

See referee reports
Despite prompt initiation of appropriate antibiotic treatment and intensive clinical monitoring, the patient failed to improve this hospitalization and developed sudden pulmonary edema and worsening aortic regurgitation on repeat transthoracic echo and unfortunately died due to rapid deterioration before surgery. As per family's wishes, an autopsy was not performed.

Discussion
Aerococcus urinae is a gram-positive, catalase-negative coccus which grows in clusters. It is mostly associated with urinary tract infections in elderly men, especially in the setting of structural abnormalities, e.g. BPH, urethral strictures and nephrolithiasis. It has been associated with culture-negative infective endocarditis 3 . It is reported to be sensitive to penicillins/cephalosporins and resistant to sulfonamides and aminoglycosides 4 . By now, more than 40 cases of IE caused by Aerococcus urinae have been reported 5 likely due to improvements in diagnostics.
Despite the fact that Aerococcus urinae is rare organism causing infective endocarditis, most cases respond well to antibiotic therapy and surgery is often not needed 2 . The indications for surgical intervention for PVE include severe prosthetic dysfunction, severe heart failure, large vegetation, and abscess or peri-valvular involvement 6 . This case highlights the importance of source control by expediting prosthesis removal in the presence of overt symptoms of worsening cardiac failure and worsening prosthesis dysfunction (regurgitation in this case), as medical therapy alone may not be sufficient to effectively treat Aerococcus urinae IE despite appropriate sensitivities. Early identification is crucial and can be lifesaving. The main problem is current diagnostic testing for microorganisms -whereas partial 16S rRNA gene sequencing analysis would be the most time-efficient method, it's rarely done, as the expertise is limited and costs are high. Recently, there is good evidence for the use of MALDI-TOF 7,8 due to increased detection rates, even in direct comparison to 16s sequencing.
In conclusion, Aerococcus urinae has been increasingly identified as the cause of infective endocarditis due to advancement in isolation methods. Therefore establishing a concise and broadly acknowledged protocol for diagnosis up to patient management is critical.

Consent
Written informed consent for publication of their clinical details was obtained from the patient. Permission was also granted from a next of kin for publication of the manuscript.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work. Thank you very much for your helpful feedback. We rephrased the suggested points throughout the article. Unfortunately we were not able to assess the points listed in the case report in our patient, however our aim was to underline the need for new techniques (like MALDI-TOF) in order to make the correct diagnosis in a timely manner. A fatal case of IE caused by Aerococcus urinae, in a 75-year-old man with a bioprosthetic aortic valve is presented and discussed. Very precise and covering comments have been given by reviewer 1. Microbiological data should be examined thouroughly and extended. Language correction seems indicated. The following comments can be added.

1) Abstract:
It is always important to also having focus on more rare etiologies of IE. In the abstract it is stated that the mortality rate is high. This is suggested to be modified to: Initial descriptions of collections of IE cases with A. urinae demonstrated a high morbidity and mortality rate, whereas a recent Swedish epidemiological study could not retrieve this. 2. A diagnosis of IE is established through the Dukes criteria, I suggest a reference to Li is given . Symptoms and chest X-ray are irrelevant for the diagnostic process. Please modify introduction.

A new reference was added to diagnose IE based on Dukes criteria or their modifications
3. In the case description it is twice stated that the patient has sepsis. Sepsis-3 criteria are not fulfilled. Please rephrase.

The cultures grew
How was the species determination performed? How many A. urinae. cultures? MIC for ampicillin and gentamycin should be given.

MICs for ampicillin and gentamicin added, description added about blood cultures
5. It is claimed that TEE demonstrates a "moderate aortic regurgitation due to a large mobile vegetation". It is important if the regurgitation was paravalvular or through the valves. Maximum size of the vegetation is also crucial since this is important for establishing the indication for operation. Left ventricular function should also be commented on as well as if there were signs of vegetations on the pacemaker cable.

Transesophgeal echo description expanded, commented on LV and pacemaker lead.
6. It is claimed that ampi+genta was commenced according to local guidelines. For which bacterial species are these guidelines meant. The use of aminoglycosides in this condition is controversial . Hospital guidelines for suspected/possible IE were followed 7. How was "progressive aortic regurgitation verified? Could pacemaker failure have played a role?
Repeat transthoracic echo showed worsening of regurgitation; this is added to the case 8. Why was the patient not moved for emergency surgery when he deteriorated? This seem like an avoidable fatality! Deterioration was sudden and rapid, arrangements were made but patient died before the 1 2 1 Deterioration was sudden and rapid, arrangements were made but patient died before the surgery 9. In the discussion it is claimed that there are only 20 reports. This is not true . Cases up until 2015 are summarized in a review .

Updated number of Aerococcus urinae IE reported
10. Surgical intervention is claimed to be common in the discussion with a quote to Wang. Please read and quote Sunnerhagen instead . Surgery is relatively rarely needed.

Reference added to show that surgery in most cases is not indicated
11. "Large persistent vegetation" is claimed as an indication for surgery. Large is enough.

"
The presence of vegetation on the valve created a consistent source of bacteria that could embolize and can serve as a source of sepsis." This statement has nothing to do with the current case and should be omitted.

"
The main problem is current diagnostic testing for microorganisms-whereas 16s sequencing would be the most time-efficient method, it's rarely done, as the expertise is limited and costs… and so on" This is irrelevant for the case since the reason to operate is not dependent on microbiological diagnostics. Irrespective of the causative pathogen this patient would have been saved by timely heart surgery. This is kept; we wish our readers to know that improved methods of isolation are important and could help with management 14. The claim "In conclusion, Aerococcus urinae used to be a rare cause of IE but rates have been increasing significantly within the last 10 years." Lacks support and should be deleted.
has been increasingly REPORTED as a cause of IE but incidence is likely A. urinae unchanged.
This is now added that that increase in reported cases is due to better isolation methods.
15. In discussing Duke criteria in the case presentation one must keep in mind that in 2/2 A. urinae cultures (4/4 bottles) only fulfill Duke criteria if the cultures were taken with

Agreed
No competing interests were disclosed. Competing Interests: 1 3 1 I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
Author Response 13 Feb 2018 , Yale University, New Haven, USA Carina Dehner 1) Abstract: -It is always important to also having focus on more rare etiologies of IE. In the abstract it is stated that the mortality rate is high. This is suggested to be modified to: Initial descriptions of collections of IE cases with A. urinae demonstrated a high morbidity and mortality rate, whereas a recent Swedish epidemiological study could not retrieve this. New reference to the introduction was added to highlight the better outcome 2) Introduction: -Dukes criteria should be mentioned.

-New references added to mention Duke's criteria or its modifications
-There is not a species named Streptococcus viridans.

·
Recent diagnostic improvements should be included, especially MALDI-TOF mass spectrometry. Added in abstract -a gram-positive, catalase-negative Correction made 3) Case description: Specific description of PM electrode findings should be given.

Included in description, PM lead was not involved.
Microbiological data are very scarce. Blood-culture system and number of positive bottles should be given. Likewise identification criteria and susceptibility methods and results, including MIC values of relevant antibiotics should be given.